A. Tai

VARIABILITY OF TARGET AND NORMAL STRUCTURE DELINEATION FOR BREAST CANCER RADIOTHERAPY : AN RTOG MULTI-INSTITUTIONAL AND MULTIOBSERVER STUDY

PURPOSE To quantify the multi-institutional and multiobserver variability of target and organ-at-risk (OAR) delineation for breast-cancer radiotherapy (RT) and its dosimetric impact as the first step of a Radiation Therapy Oncology Group effort to establish a breast cancer atlas. METHODS AND MATERIALS Nine radiation oncologists specializing in breast RT from eight institutions independently delineated targets (e.g., lumpectomy cavity, boost planning target volume, breast, supraclavicular, axillary and internal mammary nodes, chest wall) and OARs (e.g., heart, lung) on the same CT images of three representative breast cancer patients. Interobserver differences in structure delineation were quantified regarding volume, distance between centers of mass, percent overlap, and average surface distance. Mean, median, and standard deviation for these quantities were calculated for all possible combinations. To assess the impact of these variations on treatment planning, representative dosimetric plans based on observer-specific contours were generated. RESULTS Variability in contouring the targets and OARs between the institutions and observers was substantial. Structure overlaps were as low as 10%, and volume variations had standard deviations up to 60%. The large variability was related both to differences in opinion regarding target and OAR boundaries and approach to incorporation of setup uncertainty and dosimetric limitations in target delineation. These interobserver differences result in substantial variations in dosimetric planning for breast RT. CONCLUSIONS Differences in target and OAR delineation for breast irradiation between institutions/observers appear to be clinically and dosimetrically significant. A systematic consensus is highly desirable, particularly in the era of intensity-modulated and image-guided RT.

Estimate of Radiobiologic Parameters From Clinical Data for Biologically Based Treatment Planning for Liver Irradiation

PURPOSE The Radiation Therapy Oncology Group (RTOG) is initiating a few new hypofractionation regimens (RTOG 0438) to treat liver cancer patients. To evaluate the radiobiologic equivalence between different regimens requires reliable radiobiologic parameters. The purpose of this work is to estimate a plausible set of such parameters for liver tumors and to design new optimized dose fractionation schemes to increase patient survival. METHODS AND MATERIALS A model was developed to fit clinical survival data from irradiation of a series of primary liver patients. The model consists of six parameters including radiosensitivity parameters alpha and alpha/beta, potential doubling time T(d). Using this model together with the Lyman model for calculations of the normal tissue complication probability, we designed a series of hypofractionated treatment strategies for liver irradiation. RESULTS The radiobiologic parameters for liver tumors were estimated to be: alpha/beta = 15.0 +/- 2.0 Gy, alpha = 0.010 +/- 0.001 Gy (-1), T(d) = 128 +/- 12 day. By calculating the biologically effective dose using the obtained parameters, it is found that for liver patients with an effective liver volume of approximately 45% the dose fractionation regimens suggested in RTOG 0438 can be escalated to higher dose for improved patient survival ( approximately 80% at 1 year) while keeping the normal tissue complication probability to less than 10%. CONCLUSIONS A plausible set of radiobiologic parameters has been obtained based on clinical data. These parameters may be used for radiation treatment planning of liver tumors, in particular, for the design of new treatment regimens aimed at dose escalation.

Development of an online adaptive solution to account for inter- and intra-fractional variations

PURPOSE The current IGRT repositioning cannot fully account for the organ deformation and rotation. We introduce a comprehensive solution using gated IMRT with online adaptive replanning to manage both inter- and intra-fractional variations. METHODS AND MATERIALS The solution includes (1) generating respiration-gated IMRT plans based on 4DCT, (2) acquiring daily gated CT in treatment position prior to the treatment using a diagnostic-quality in-room CT (CTVision, Siemens) with the same gating window as that for the planning CT, (3) performing online repositioning or adaptive replanning based on the gated CT of the day, and (4) delivering the treatment with gating. The entire solution is demonstrated with RT data from 10 selected pancreatic cancer cases. The dosimetric impact of various advanced delivery technologies was investigated. RESULTS The online adaptive replanning based on the CT of the day combining with gating significantly improves normal tissue sparing during RT for pancreatic cancer. As the complexity of the delivery technology increases from no IGRT to with IGRT, gating and online adaptive replanning, the inter- and intra-fractional variations can be accounted for with increased adequacy. CONCLUSION The online adaptive replanning technique based on daily respiration-gated diagnostic-quality CT combined with gated delivery can effectively correct for inter- and intra-fraction variations during radiation therapy.

Extrapolation of Normal Tissue Complication Probability for Different Fractionations in Liver Irradiation

PURPOSE The ability to predict normal tissue complication probability (NTCP) is essential for NTCP-based treatment planning. The purpose of this work is to estimate the Lyman NTCP model parameters for liver irradiation from published clinical data of different fractionation regimens. A new expression of normalized total dose (NTD) is proposed to convert NTCP data between different treatment schemes. METHOD AND MATERIALS The NTCP data of radiation- induced liver disease (RILD) from external beam radiation therapy for primary liver cancer patients were selected for analysis. The data were collected from 4 institutions for tumor sizes in the range of of 8-10 cm. The dose per fraction ranged from 1.5 Gy to 6 Gy. A modified linear-quadratic model with two components corresponding to radiosensitive and radioresistant cells in the normal liver tissue was proposed to understand the new NTD formalism. RESULTS There are five parameters in the model: TD(50), m, n, alpha/beta and f. With two parameters n and alpha/beta fixed to be 1.0 and 2.0 Gy, respectively, the extracted parameters from the fitting are TD(50)(1) = 40.3 +/- 8.4Gy, m =0.36 +/- 0.09, f = 0.156 +/- 0.074 Gy and TD(50)(1) = 23.9 +/- 5.3Gy, m = 0.41 +/- 0.15, f = 0.0 +/- 0.04 Gy for patients with liver cirrhosis scores of Child-Pugh A and Child-Pugh B, respectively. The fitting results showed that the liver cirrhosis score significantly affects fractional dose dependence of NTD. CONCLUSION The Lyman parameters generated presently and the new form of NTD may be used to predict NTCP for treatment planning of innovative liver irradiation with different fractionations, such as hypofractioned stereotactic body radiation therapy.

Gated treatment delivery verification with on-line megavoltage fluoroscopy.

PURPOSE To develop and clinically demonstrate the use of on-line real-time megavoltage (MV) fluoroscopy for gated treatment delivery verification. METHODS AND MATERIALS Megavoltage fluoroscopy (MVF) image sequences were acquired using a flat panel equipped for MV cone-beam CT in synchrony with the respiratory signal obtained from the Anzai gating device. The MVF images can be obtained immediately before or during gated treatment delivery. A prototype software tool (named RTReg4D) was developed to register MVF images with phase-sequenced digitally reconstructed radiograph images generated from the treatment planning system based on four-dimensional CT. The image registration can be used to reposition the patient before or during treatment delivery. To demonstrate the reliability and clinical usefulness, the system was first tested using a thoracic phantom and then prospectively in actual patient treatments under an institutional review board-approved protocol. RESULTS The quality of the MVF images for lung tumors is adequate for image registration with phase-sequenced digitally reconstructed radiographs. The MVF was found to be useful for monitoring inter- and intrafractional variations of tumor positions. With the planning target volume contour displayed on the MVF images, the system can verify whether the moving target stays within the planning target volume margin during gated delivery. CONCLUSIONS The use of MVF images was found to be clinically effective in detecting discrepancies in tumor location before and during respiration-gated treatment delivery. The tools and process developed can be useful for gated treatment delivery verification.

Management of Respiration-Induced Motion With 4-Dimensional Computed Tomography (4DCT) for Pancreas Irradiation

PURPOSE The purposes of this study were to quantify respiration-induced organ motions for pancreatic cancer patients and to explore strategies to account for these motions. METHODS AND MATERIALS Both 3-dimensional computed tomography (3DCT) and 4-dimensional computed tomography (4DCT) scans were acquired sequentially for 15 pancreatic cancer patients, including 10 randomly selected patients and 5 patients selected from a subgroup of patients with large tumor respiratory motions. 3DCTs were fused with 2 sets of 4DCT data at the end of exhale phase (50%) and the end of inhale phase (0%). The target was delineated on the 50% and 0% phase CT sets, and the organs at risk were drawn on the 3DCT. These contours were populated to the CT sets at other respiratory phases based on deformable image registration. Internal target volumes (ITV) were generated by tracing the target contours of all phases (ITV10), 3 phases of 0%, 20% and 50% (ITV3), and 2 phases of 0% and 50% (ITV2). ITVs generated from phase images were compared using percentage of volume overlap, Dice coefficient, geometric centers, and average surface distance. RESULTS Volume variations of pancreas, kidneys, and liver as a function of respiratory phases were small (<5%) during respiration. For the 10 randomly selected patients, peak-to-peak amplitudes of liver, left kidney, right kidney, and the target along the superior-inferior (SI) direction were 7.9 ± 3.2 mm, 7.1 ± 3.1 mm, 5.7 ± 3.2 mm, and 5.9 ± 2.8 mm, respectively. The percentage of volume overlap and Dice coefficient were 92% ± 1% and 96% ± 1% between ITV10 and ITV2 and 96% ± 1% and 98% ± 1% between ITV10 and ITV3, respectively. The percentage of volume overlap between ITV10 and ITV3 was 93.6 ± 1.1 for patients with tumor motion >8 mm. CONCLUSIONS Appropriate motion management strategies are proposed for radiation treatment planning of pancreatic tumors based on magnitudes of tumor respiratory motions.

Tumor control probability modeling for stereotactic body radiation therapy of early-stage lung cancer using multiple bio-physical models

This work is to analyze pooled clinical data using different radiobiological models and to understand the relationship between biologically effective dose (BED) and tumor control probability (TCP) for stereotactic body radiotherapy (SBRT) of early-stage non-small cell lung cancer (NSCLC). The clinical data of 1-, 2-, 3-, and 5-year actuarial or Kaplan-Meier TCP from 46 selected studies were collected for SBRT of NSCLC in the literature. The TCP data were separated for Stage T1 and T2 tumors if possible, otherwise collected for combined stages. BED was calculated at isocenters using six radiobiological models. For each model, the independent model parameters were determined from a fit to the TCP data using the least chi-square (χ2) method with either one set of parameters regardless of tumor stages or two sets for T1 and T2 tumors separately. The fits to the clinic data yield consistent results of large α/β ratios of about 20Gy for all models investigated. The regrowth model that accounts for the tumor repopulation and heterogeneity leads to a better fit to the data, compared to other 5 models where the fits were indistinguishable between the models. The models based on the fitting parameters predict that the T2 tumors require about additional 1Gy physical dose at isocenters per fraction (⩽5 fractions) to achieve the optimal TCP when compared to the T1 tumors. In conclusion, this systematic analysis of a large set of published clinical data using different radiobiological models shows that local TCP for SBRT of early-stage NSCLC has strong dependence on BED with large α/β ratios of about 20Gy. The six models predict that a BED (calculated with α/β of 20) of 90Gy is sufficient to achieve TCP⩾95%. Among the models considered, the regrowth model leads to a better fit to the clinical data.

SU‐E‐T‐256: Radiation Dose Responses for Chemoradiation Therapy of Pancreatic Cancer: An Analysis of Compiled Clinical Data Using Biophysical Models

PURPOSE We have analyzed recent clinical data obtained from chemoradiation of unresectable, locally advanced pancreatic cancer in order to examine possible benefits from radiotherapy (RT) dose escalation as well as to propose possible dose escalated fractionation schemes. METHODS A modified linear quadratic (LQ) model was used to fit clinical tumor response data from chemoradiation treatments using different fractionations. Biophysical radiosensitivy parameters, a and α/β, tumor potential doubling time, Td, and delay time for tumor doubling during treatment, Tk, were extracted from the fits and were used to calculate feasible fractionation schemes for dose escalations. RESULTS Examination of published data from 20 institutions showed no clear indication of improved survival with raised radiation dose. However, an enhancement in tumor response was observed for higher irradiation doses, an important and promising clinical Result with respect to palliation and quality of life. The radiobiological parameter estimates obtained from the analysis are: α/β = 10 ± 3 Gy, a = 0.010 ± 0.003 Gŷ-1, Td = 56 ± 5 days and Tk = 7 ± 2 days. Possible dose escalation schemes are proposed based on the calculation of the biologically equivalent dose (BED) required for a 50% tumor response rate. CONCLUSIONS From the point of view of tumor response, escalation of the administered radiation dose leads to a potential clinical benefit, which when combined with normal tissue complication analyses may Result in improved treatments for certain patients with advanced pancreatic cancer. Based on this analysis, a dose escalation trial with 2.25 Gy/fraction up to 69.75 Gy is being initiated for unresectable pancreatic cancer at our institution. Partially supported by MCW Cancer Center Meinerz Foundation.

Radiation dose responses for chemoradiation therapy of pancreatic cancer: An analysis of compiled clinical data using biophysical models

PURPOSE We analyzed recent clinical data obtained from chemoradiation of unresectable, locally advanced pancreatic cancer (LAPC) in order to examine possible benefits from radiation therapy dose escalation. METHODS AND MATERIALS A modified linear quadratic model was used to fit clinical tumor response and survival data of chemoradiation treatments for LAPC reported from 20 institutions. Biophysical radiosensitivity parameters were extracted from the fits. RESULTS Examination of the clinical data demonstrated an enhancement in tumor response with higher irradiation dose, an important clinical result for palliation and quality of life. Little indication of improvement in 1-year survival with increased radiation dose was observed. Possible dose escalation schemes are proposed based on calculations of the biologically effective dose required for a 50% tumor response rate. CONCLUSIONS Based on the evaluation of tumor response data, the escalation of radiation dose presents potential clinical benefits which when combined with normal tissue complication analyses may result in improved treatment outcome for locally advanced pancreatic cancer patients.

Determination of Internal Target Volume for Radiation Treatment Planning of Esophageal Cancer by Using 4-Dimensional Computed Tomography (4DCT)

PURPOSE To determine an efficient strategy for the generation of the internal target volume (ITV) for radiation treatment planning for esophageal cancer using 4-dimensional computed tomography (4DCT). METHODS AND MATERIALS 4DCT sets acquired for 20 patients with esophageal carcinoma were analyzed. Each of the 4DCT sets was binned into 10 respiratory phases. For each patient, the gross tumor volume (GTV) was delineated on the 4DCT set at each phase. Various strategies to derive ITV were explored, including the volume from the maximum intensity projection (MIP; ITV_MIP), unions of the GTVs from selected multiple phases ITV2 (0% and 50% phases), ITV3 (ITV2 plus 80%), and ITV4 (ITV3 plus 60%), as well as the volumes expanded from ITV2 and ITV3 with a uniform margin. These ITVs were compared to ITV10 (the union of the GTVs for all 10 phases) and the differences were measured with the overlap ratio (OR) and relative volume ratio (RVR) relative to ITV10 (ITVx/ITV10). RESULTS For all patients studied, the average GTV from a single phase was 84.9% of ITV10. The average ORs were 91.2%, 91.3%, 94.5%, and 96.4% for ITV_MIP, ITV2, ITV3, and ITV4, respectively. Low ORs were associated with irregular breathing patterns. ITV3s plus 1 mm uniform margins (ITV3+1) led to an average OR of 98.1% and an average RVR of 106.4%. CONCLUSIONS The ITV generated directly from MIP underestimates the range of the respiration motion for esophageal cancer. The ITV generated from 3 phases (ITV3) may be used for regular breathers, whereas the ITV generated from 4 phases (ITV4) or ITV3 plus a 1-mm uniform margin may be applied for irregular breathers.